There is considerable evidence that neurotensin (NT)-containing neuronal systems are altered in schizophrenia and mediate some of the effects of antipsychotic drugs (APDs). Much of the available literature on the manifold interactions of NT and dopamine (DA)-containing neural circuits, as well as the role of this neuropeptidergic system in the biology of schizophrenia and in the action of APDs was generated by research supported by this grant now completing its 28th year of funding. Whether NT neuronal systems play a seminal role in mediating the effects of all APDs or whether, as our preliminary data generated during the present funding period suggests, that some atypical APDs are NTergic-dependent and others are not, remains an important unanswered question. This research area is one major focus of the current proposal. Using two well characterized and validated sensorimotor gating paradigms that readily quantify APD effects, prepulse inhibition (PPI) of the acoustic startle response and latent inhibition (Ll), we determine whether APDs can be classified as NT-dependent and NT-independent. NT-dependence may represent a novel method of classifying APDs. In addition, we address the critical and related questions of which NT receptor subtype mediates the APD-like effects of NT and what characteristic of APDs renders them dependent on NT neurotransmission. Because of the lack of truly receptor specific NT receptor antagonists, the NT receptor subtype mediating the APD-like effects of NT will be identified using two innovative approaches. First, experiments utilizing viral vectors over expressing the NTT and NT2 receptors will examine the brain region specific effects of modulating NT receptor subtype specific expression. Viral vectors expressing the antisense RNA to the NTT and NT2 receptors will also be generated in order to produce brain region specific knockdown of the NT receptor subtypes. Second, the efficacy of APDs in the PPI paradigm will be compared in NT-, and NT2 receptor knockout mice. Lastly, APD effects on the NT system and APD modulation of PPI are dependent on estrous cycle stage in female rats. Therefore, the role of NT in estrous cycle regulation of PPI and APD effects on PPI will be assessed. Elucidation of the role of NTergic systems in the mechanism of action of APDs may be a critical key in understanding effective APD therapy and has the potential to assist in the development of more effective treatments of psychotic disorders. This research is particularly timely as a landmark antipsychotic drug effictiveness study (CATIE, see within) has recently been published documenting the need for novel APDs with greater efficacy and tolerability. Drugs that act upon NT circuits represent just such a novel research direction.